Medical uses

Schizophrenia

Risperidone is effective in treating the acute exacerbations of schizophrenia.[9][10] A 2013 study compared 15 antipsychotic drugs in treating schizophrenia. Risperidone was ranked fourth, 11% more effective than paliperidone (5th), 20-23% more effective than haloperidol, quetiapine, and aripiprazole, and 36% less effective than clozapine (1st).[11]

Studies evaluating the utility of risperidone by mouth for maintenance therapy have reached varying conclusions. A 2012 systematic review concluded that there is strong evidence that risperidone is more effective than all first generation antipsychotics other than haloperidol, but that evidence directly supporting its superiority to placebo is equivocal.[12] A 2011 review concluded that risperidone is more effective in relapse prevention than other first and second generation antipsychotics with the exception of olanzapine and clozapine.[13] A 2016 Cochrane review suggests that risperidone reduces the overall symptoms of schizophrenia, but firm conclusions are difficult to make due to very low quality evidence. Data and information are scarce, poorly reported and probably biased in favour of risperidone, with about half of the included trials developed by drug companies. The article raises concerns regarding the serious side effects of risperidone, such as parkinsonism.[14] A 2011 Cochrane review compared risperidone with other atypical antipsychotics such as olanzapine for schizophrenia:[15]

Summary

Risperidone seems to produce somewhat more extrapyramidal side effects and clearly more prolactin increase than most other atypical antipsychotics. It may also differ from other compounds in the occurrence of other adverse effects such as weight gain, metabolic problems, cardiac effects, sedation and seizures. Nevertheless, the large proportion of participants leaving studies early and incomplete reporting of outcomes makes it difficult to draw firm conclusions.[15]

Outcome

Findings in words

Findings in numbers

Quality of evidence

Global state

No clinically significant response

Risperidone is not clearly different when compared to olanzapine. Data supporting this finding are based on moderate quality evidence.

On average, people receiving risperidone scored slightly higher (worse) than people treated with olanzapine but there was no clear difference between the groups. The meaning of this in day-to-day care is unclear. This finding is based on data of low quality.

On average, people receiving risperidone scored higher than people treated with olanzapine. There was no clear difference between the groups. The meaning of this in day-to-day care is unclear. This finding is based on data of moderate quality.

Long-acting injectable formulations of antipsychotic drugs provide improved compliance with therapy and reduce relapse rates relative to oral formulations.[16][17] The efficacy of risperidone long acting injection appears to be similar to that of long acting injectable forms of first generation antipsychotics.[18]

Bipolar disorder

Second generation antipsychotics, including risperidone, are effective in the treatment of manic symptoms in acute manic or mixed exacerbations of bipolar disorder.[19][20][21] In children and adolescents, risperidone may be more effective than lithium or divalproex, but has more metabolic side effects.[22] As maintenance therapy, long-acting injectable risperidone is effective for the prevention of manic episodes but not depressive episodes.[23] The long-acting injectable form of risperidone may be advantageous over long acting first generation antipsychotics, as it is better tolerated (fewer extrapyramidal effects) and because long acting injectable formulations of first generation antipsychotics may increase the risk of depression.[24]

Autism

Compared to placebo, risperidone treatment reduces certain problematic behaviors in autistic children, including aggression toward others, self-injury, temper tantrums, and rapid mood changes. The evidence for its efficacy appears to be greater than that for alternative pharmacological treatments.[25] Weight gain is an important adverse effect.[26][27] Some authors recommend limiting the use of risperidone and aripiprazole to those with the most challenging behavioral disturbances in order to minimize the risk of drug-induced adverse effects.[28] Evidence for the efficacy of risperidone in autistic adolescents and young adults is less persuasive.[29]

Other uses

Risperidone has not demonstrated a benefit in the treatment of eating disorders or personality disorders.[31]

While antipsychotic medications such as risperidone have a slight benefit in people with dementia, they have been linked to higher incidences of death and stroke.[31] Because of this increased risk of death, treatment of dementia-related psychosis with risperidone is not FDA approved.[32]

While atypical antipsychotics appear to have a lower rate of movement problems as compared to typical antipsychotics, risperidone has a high risk of movement problems among the atypicals.[34][35] Atypical antipsychotics however are associated with a greater amount of weight gain.[35]

Drug interactions

Carbamazepine and other enzyme inducers may reduce plasma levels of risperidone.[36] If a person is taking both carbamazepine and risperidone, the dose of risperidone will likely need to be increased. The new dose should not be more than twice the patient's original dose.[37]

CYP2D6 inhibitors, such as SSRI medications, may increase plasma levels of risperidone.[36]

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.[38] Some have argued the additional somatic and psychiatric symptoms associated with dopaminergic super-sensitivity, including dyskinesia and acute psychosis, are common features of withdrawal in individuals treated with neuroleptics.[39][40][41][42] This has led some to suggest the withdrawal process might itself be schizomimetic, producing schizophrenia-like symptoms even in previously healthy patients, indicating a possible pharmacological origin of mental illness in a yet unknown percentage of patients currently and previously treated with antipsychotics. This question is unresolved, and remains a highly controversial issue among professionals in the medical and mental health communities, as well the public.[43]

Dementia

Older people with dementia-related psychosis are at a higher risk of death if they take risperidone compared to those who do not. Most deaths are related to heart problems or infections.[37]

Dopamine receptors: This drug is an antagonist of the D1 (D1, and D5) as well as the D2 family (D2, D3 and D4) receptors, with 70-fold selectivity for the D2 family. This drug has "tight binding" properties, which means it has a long half-life and like other antipsychotics, risperidone blocks the mesolimbic pathway, the prefrontal cortex limbic pathway, and the tuberoinfundibular pathway in the central nervous system. Risperidone may induce extrapyramidal side effects, akathisia and tremors, associated with diminished dopaminergic activity in the striatum. It can also cause sexual side effects, galactorrhoea, infertility, gynecomastia and, with chronic use reduced bone mineral density leading to breaks, all of which are associated with increased prolactin secretion.[46]

Serotonin receptors: Its action at these receptors may be responsible for its lower extrapyramidal side effect liability (via the 5-HT2A/2C receptors) and improved negative symptom control compared to typical antipsychotics such as haloperidol for instance. Its antagonistic actions at the 5-HT2C receptor may account, in part, for its weight gain liability.

Pharmacokinetics

Risperidone undergoes hepatic metabolism and renal excretion. Lower doses are recommended for patients with severe liver and kidney disease.[32] The active metabolite of risperidone, paliperidone, is also used as an antipsychotic.[49]

Society and culture

Regulatory status

Risperidone was approved by the United States Food and Drug Administration (FDA) in 1993 for the treatment of schizophrenia.[50] In 2003, the FDA approved risperidone for the short-term treatment of the mixed and manic states associated with bipolar disorder. In 2006, the FDA approved risperidone for the treatment of irritability in autistic children and adolescents.[51] On August 22, 2007, risperidone was approved as the only drug agent available for treatment of schizophrenia in youths, ages 13–17; it was also approved that same day for treatment of bipolar disorder in youths and children, ages 10–17, joining lithium. The FDA's decision was based in part on a study of autistic people with severe and enduring problems of violent meltdowns, aggression, and self-injury; risperidone is not recommended for autistic people with mild aggression and explosive behavior without an enduring pattern.[52]

Availability

Janssen's patent on risperidone expired on December 29, 2003, opening the market for cheaper generic versions from other companies, and Janssen's exclusive marketing rights expired on June 29, 2004 (the result of a pediatric extension). It is available under many brand names worldwide.[1]

Risperidone is available as a tablet, an oral solution, and an ampule, which is a depot injection.[1]

In November 2013, J&J was fined $2.2 billion for illegally marketing risperidone for use in people with dementia.[56]

J&J has faced numerous civil lawsuits on behalf of children who were prescribed risperidone who grew breasts (a condition called gynecomastia); as of July 2016 there were about 1,500 cases in Pennsylvania state court in Philadelphia, and there had been a February 2015 verdict against J&J with $2.5 million awarded to a man from Alabama, a $1.75M verdict against J&J that November, and in 2016 a $70 million verdict against J&J.[57]

In 2015, Steven Brill posted a 15-part investigative journalism piece on J&J in Huffington Post, called "America's most admired lawbreaker", which was focused on J&J's marketing of risperidone.[58][59]

^Scahill L (July 2008). "How do I decide whether or not to use medication for my child with autism? Should I try behavior therapy first?". Journal of Autism and Developmental Disorders. 38 (6): 1197–8. doi:10.1007/s10803-008-0573-7. PMID18463973.